Pancreatic adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the fourth leading cause of cancer-related death in the United States. It is an extremely slow growing tumor. PDAC normally remains undetectable until late in the disease process, due in part to the physical location of the pancreas. It is situated behind the stomach at the back of the retroperitoneal space, overlaying the aorta, vena cava, and spine, deep inside the body. Because of the location of the pancreas, a computed tomography or magnetic resonance imaging scan is typically needed to detect a lesion, so it may not be discovered until the patient develop symptoms. PDACs located in the head of the pancreas may obstruct the bile duct, resulting in jaundice. Approximately 80 percent of PDAC cases present with this painless jaundice. When the lesion is located in the body or tail of the pancreas, however, the first symptom is likely to be pain associated with invasion of the spleen or stomach, occurring much later in the course of the disease.
Surgery is the only potentially curative treatment for PDAC, but due to the late stage at diagnosis many patients will not be good candidates for surgery. Tumor staging, based on evidence of peritoneal or hepatic metastases and radiological findings of blood vessel involvement, classifies tumors as resectable, borderline resectable, or nonresectable. By these criteria, only 25 to 30 percent of tumors are considered operable or resectable at diagnosis. Thus, treatment with curative intent is very difficult for most patients. Two main areas of research, then, are efforts to increase earlier detection and improve treatment.
Pinpointing biomarkers to improve detection, treatment and monitoring of pancreatic cancer
Biomarkers are any measurable biological molecule that can be found in the tumor, blood or other bodily fluids that signals an abnormal process, such as cancer. Measurement of biomarkers in blood is considered a less invasive method to detect cancer at an early state, measure relapse of disease, or determine optimum treatment for a patient. A number of different classes of biomarkers have been studied. Two translational studies funded by the Baylor Charles A. Sammons Cancer Center's Swim Across America Innovative Clinical Trials Center (SAA-ICTC) at Baylor University Medical Center are focused on identifying more precise biomarkers for the early detection, disease monitoring and optimum treatment for pancreatic cancer. These studies utilize two types of analysis—cell-free circulating tumor-specific DNA analysis (ctDNA) and microRNA (miRNA) analysis—looking for the presence of these biomarkers in the blood of patients with pancreatic tumors.
ctDNA analysis for personalized monitoring of pancreatic cancer
Scott Celinski, MD, codirector of the Baylor Pancreatic Cancer Research and Treatment Center and lead investigator, and Muhammed Murtaza, MD, PhD, codirector of the Translational Genomics Research Institute (TGen) Center for Noninvasive Diagnostics and coinvestigator, launched a pilot study to test whether ctDNA in plasma can be used as a personalized biomarker of tumor burden in patients with PDAC. Researchers had previously shown that ctDNA may be useful for monitoring tumor burden and disease progression in a multitude of solid cancers.
To date, the pilot study has enrolled more than 10 patients with PDAC since December 2010. For each patient, serial plasma samples have been collected pre- and postoperatively, along with samples from the resected tumor specimen for genomic analyses. Based on tumor analysis, the researchers develop molecular assays specific to each patient's cancer for personalized monitoring of tumor burden. The goal of the study is to follow each patient longitudinally to determine if these plasma ctDNAs correlate with the presence of the tumor and if there is a drop in the patient- and PDAC-specific biomarkers after removal of the tumor. If ctDNAs do track with the presence or absence of tumor, then they will follow these ctDNAs to see if they change at the time of cancer relapse. Researchers hope that select ctDNAs will allow them to track tumor burden in real time, as the documented half-life in other cancer types is less than two hours. They continue to collect plasma and urine samples from the enrolled patients. If initial findings are encouraging, the goal is to pursue extramural grant sources to expand analysis with a larger set of patients.
"So far, we have made progress in two aspects: clinical accrual and technology development," Dr. Murtaza said. "Together with additional support from other grants, we are developing a novel method for personalized ctDNA monitoring to target multiple cancer mutations from each patient's tumor simultaneously. This will enable greater sensitivity and precision in liquid biopsy tests. We are in the final stages of optimizing this method and hope to test its clinical relevance in this pancreatic cancer study shortly."
"Cell-free DNA fragments contributed by a tumor into blood can be measured using molecular analysis for cancer-specific somatic mutations," Dr. Murtaza explained. "ctDNA is therefore an inherently cancer-specific biomarker for solid cancers such as pancreatic cancer. Potential applications of ctDNA analysis include personalized monitoring of tumor burden to detect treatment response, tumor dynamics, minimal residual disease, and relapse, as well as minimally invasive serial investigation of the cancer genome for molecular stratification and tracking subclonal evolution."
During the pilot study, investigators are exploring if personalized ctDNA tracking can be used for assessment of postoperative residual disease, early detection of systemic relapse and disease progression and rational and informed selection and scheduling of adjuvant chemotherapy.
Next-generation sequencing for detection of miRNA biomarkers for pancreatic cancer
Spurred by the dismal five-year survival rate for pancreatic cancer patients, Ajay Goel, PhD, investigator and director of the Center for Gastrointestinal Research and director of the Center for Translational Genomics and Oncology at Baylor University Medical Center, launched a study to develop another type of tumor-associated nucleic acid in circulation as a biomarker for PDAC miRNAs. Utilizing the same patient samples as in the study of Drs. Murtaza and Celinski, along with the same patient tracking goals, Dr. Goel used innovative strategies that included next-generation sequencing for genome-wide discovery of highly specific miRNAs in both tissue and serum.
Researchers had previously shown that circulating miRNAs (~22 nucleotides in length) may be useful for monitoring tumor burden and disease progression in a multitude of solid cancers. Small noncoding RNAs, miRNAs, play a pivotal role in the regulation of genes known to be involved in the development of cancer. Accumulating evidence suggests that miRNAs are implicated in the tumorigenesis of every human cancer, including PDAC. As biomarkers, miRNAs are more robust than messenger RNAs, being less prone to degradation in tissues, blood, stool, and other bodily fluids.
RNA sequencing has been completed on a small group of healthy volunteers and patients with PDAC. In addition, the research team has identified a panel of miRNAs that can be detected in blood for early detection of PDAC. These initial results were recently presented at the American Gastroenterological Association's annual Digestive Disease Week. The presentation received "Abstract of Distinction" honors. Dr. Goel said the findings are being compiled in anticipation of publication in a scientific journal.
"This study combined recent advances into two areas of circulating biomarkers, ctDNA and miRNAs," explained Dr. Goel. "It leveraged the unique strengths of the exclusive tumor specificity of somatic mutations in ctDNA and the functional insights provided by miRNAs. Our goal was to combine these approaches to identify a set of biomarkers that can sensitively detect early pancreatic cancer while providing specificity for invasive cancer and reducing false-positives from precancerous lesions or nonmalignant pancreatic disease."
Unlike glycoprotein biomarkers, tumor-associated nucleic acids in circulation represent cancer activity exclusively and rely on specific markers for tumor cells such as somatic mutations. Overall, combining the tumor specificity of ctDNA and the functional insight of circulating miRNAs can provide an accurate and informative biomarker for detection, prognosis, and monitoring of pancreatic cancer and for distinguishing PDAC at early stages of development.
Plans for the future biomarker studies
It is well known that assessing treatment response and detecting relapse after surgery in patients with pancreatic cancer is challenging. With development of biomarkers specific for PDAC that can be used for liquid biopsies and disease monitoring, the goal of these studies is to optimize treatment schedules for individual patients with early stage pancreatic cancer. For example, for patients who receive neoadjuvant chemotherapy, investigators may be able to assess within a few weeks whether the patients are benefiting from this treatment or if they would be better off proceeding to surgery right away. Similarly, after patients undergo surgery, they can be monitored for cancer recurrence weeks or months earlier than imaging, potentially improving their outcomes with more timely treatment. Researchers anticipate having preliminary results from the study by 2018.
Dr. Goel and Dr. Murtaza agree that funding preliminary clinical translational studies and the setup of well-annotated patient cohorts is critical to the success of their work. Without the support of organizations like SAA, they said, it would be nearly impossible to pursue novel ideas in translational genomics because it is difficult to secure extramural peer-reviewed funding from sources like the National Institutes for Health without demonstrating preliminary results and having existing clinical cohorts and resources.
A pilot study investigating the safety of anakinra combined with standard chemotherapy regimens in patients with metastatic pancreatic ductal adenocarcinoma
Patients with chronic pancreatitis have a greater risk of developing PDAC. In pancreatitis, the pancreas is inflamed, due to the release of digestive enzymes that are normally stored in the pancreas. These digestive enzymes are activated in pancreatitis and attempt to digest the organ, causing inflammation. The presence of inflammation appears to be the key to this increased risk of cancer. Formation of pancreatic cancer is associated with a stromal desmoplastic reaction that causes a dense stroma to surround the cancer cells, making them less responsive to conventional chemotherapies. Inflammation promoting pancreatic cancer can come from many avenues, including from the interaction between the cancer cells and stroma. A number of studies have shown that secretion of interleukin (IL)-1β, a key mediator of inflammation, from cells in the stroma can confer chemoresistance to PDAC cells in vitro. Based on these and other studies, Carlos Becerra, MD, medical director of the SAA-ICTC at Baylor Sammons Cancer Center at Dallas, initiated a study to evaluate the safety of a drug called anakinra in combination with standard chemotherapy regimens in patients with PDAC. Anakinra (Kinerert) is a Food and Drug Administration–approved drug for treatment of adults with moderate to severe rheumatoid arthritis. Anakinra blocks the inflammatory action of IL-1β binding with the IL-1 receptor and prevents IL-1β from activating inflammatory pathways. Because anakinra has been deemed safe, even for treatment of neonates, the study investigated the safety and efficacy of anakinra treatment of metastatic patients with PDAC.
In addition to evaluating drug safety, the study collected preliminary immune modulation and clinical activity information, as well as information on overall survival and serious adverse events related to the study drug. A total of 16 patients with metastatic PDAC were treated with a standard regimen of chemotherapy (modified FOLFIRINOX), administered every 2 weeks. During this treatment, patients received anakinra, given as a daily self-administered subcutaneous injection, for 2 months. Most patients' tumors regressed or stopped growing. In one patient the pancreas tumor shrunk in half, decreasing from 27.5 mm to 13.3 mm after treatment with FOLFIRINOX plus anakinra, and two small lung metastases became undetectable. Of the 14 patients who completed the study, the median overall survival was 16.7 months. The range was 1.2 months for one patient who did not respond to treatment to almost 4 years for another patient.
One advantage to using anakinra in combination with the modified FOLFIRINOX regimen was that there were few additional toxicities than with the chemotherapy alone. The main reported toxicity was neutropenia. This side effect can be lessened by giving the patient a drug to stimulate the bone marrow to produce more white blood cells, thereby counteracting the effect of anakinra.
This study has been completed, and investigators are excited about the results. Investigators were encouraged by the positive effects of anakinra on participants' quality of life. One benefit was an unexpected analgesic effect during its use, which resulted in a decrease in narcotic utilization. Decreased use of narcotics allows patients to be present and interact with their family and friends, preserving their quality of life for a longer period of time. "Maintaining patient health is a key to treating this disease. For a patient to withstand chemotherapy, proper nutrition, not losing weight, and a good attitude are vital for survival," explained Dr. Becerra. "We need to do further testing of anakinra in order to develop better treatment options for PDAC."
As a follow up to this study, a second study was designed to test the efficacy of combining anakinra with a three-drug chemotherapy regimen of gemcitabine, nab-paclitaxel (Abraxane), and cisplatin in patients with metastatic or potentially resectable pancreatic cancers (the AGAP trial). The hypothesis is that there are many PDAC patients with undetected BRCA1/2 mutations, and the addition of cisplatin should result in a better tumor response in these patients. Moreover, whatever the mutation status of the patient, adding anakinra should do two things. First, it should decrease the amount of stroma in the tumor, enhancing the access of therapeutic drugs to tumor cells. Second, it should maintain or increase the well-being of PDAC patients while they are undergoing chemotherapy, thereby making them better able to tolerate these life-saving treatments. This trial is ongoing, and preliminary results reveal a high disease control rate. None of this could have been accomplished without seed funding from SAA for the first clinical trial with PDAC patients being treated with FOLFIRINOX and anakinra.